Oogenesis and embryogenesis require the precise orchestration of multiple signaling networks and molecular pathways. Perturbations in any one event can lead to a host of developmental abnormalities such as the Apert and Pfieffer syndromes and cancer. Among the crucial components are the RAS-extracellular regulated kinase (ERK) signaling pathway and Dicer and Drosha, essential mediators of small RNA biogenesis. They govern a wide array of cellular and developmental processes, including many critical aspects of oogenesis and embryogenesis. For example, in mice, loss of ERK signaling results in defective oocyte maturation and perturbed trophoblast development, while in Caenorhabditis elegans loss of ERK function disrupts oocyte differentiation and maturation, leading to sterility or early embryonic lethality. Similarly, in C. elegans and mice, loss of Dicer or Drosha disrupts oocyte meiotic maturation and embryonic development, respectively. However, the functional intersection between the RAS/ERK pathway and small RNA biogenesis remains unclear, and no studies have shown that the RAS/ERK pathway regulates the activity of Dicer or Drosha. Our work on the identification of substrates through which ERK governs germline development in Caenorhabditis elegans recently uncovered a direct, functional link between the RAS/ERK pathway and Dicer and Drosha. In a functional genomics screen, we identified Dicer and Drosha as novel, evolutionarily conserved substrates of ERK that each function in a reciprocally antagonistic manner with ERK. By generating antibodies specific to the phosphorylated form of Dicer, we also observed that ERK-mediated phosphorylation of Dicer induces it to translocate from the cytoplasm to the nucleus in the C. elegans germline;this phosphorylation event and its consequences on Dicer localization are conserved in mouse embryonic fibroblasts and human tumor cells. Therefore, the goals of our proposed study are three-fold: i) to elucidate the effect of ERK-dependent phosphorylation on the localization of Drosha;ii) to test the impact of ERK-mediated phosphorylation on Dicer and Drosha function and small RNA production;and, iii) to determine the mechanistic basis of phospho-Dicer function by identifying functional partners of the modified proteins. Given the general relevance of RAS/ERK signaling pathway and Dicer and Drosha, results from our work will likely inform multiple systems, including human oogenesis and oncogenesis. !

Public Health Relevance

This proposed project aims to investigate the role of the oncogenic RAS/Extracellular-signal regulated kinase (ERK) in regulating the tumor suppressors Dicer and Drosha, two key small RNA biogenesis enzymes. The study integrates multiple approaches ranging from classical genetics and cell biology to genomic and proteomic methods to assess the impact of ERK mediated phosphorylation on Dicer and Drosha function in vivo during Caenorhabitis elegans germline development. !

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
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Haynes, Susan R
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University of Texas MD Anderson Cancer Center
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Minogue, Amanda L; Tackett, Michael R; Atabakhsh, Elnaz et al. (2018) Functional genomic analysis identifies miRNA repertoire regulating C. elegans oocyte development. Nat Commun 9:5318
Furuta, Tokiko; Joo, Hyoe-Jin; Trimmer, Kenneth A et al. (2018) GSK-3 promotes S-phase entry and progression in C. elegans germline stem cells to maintain tissue output. Development 145:
Arur, Swathi (2017) Signaling-Mediated Regulation of Meiotic Prophase I and Transition During Oogenesis. Results Probl Cell Differ 59:101-123
Chen, Jessica Jie; Arur, Swathi (2017) Discovering Functional ERK Substrates Regulating Caenorhabditis elegans Germline Development. Methods Mol Biol 1487:317-335
Burton, Nicholas O; Furuta, Tokiko; Webster, Amy K et al. (2017) Insulin-like signalling to the maternal germline controls progeny response to osmotic stress. Nat Cell Biol 19:252-257
Das, Debabrata; Arur, Swathi (2017) Conserved insulin signaling in the regulation of oocyte growth, development, and maturation. Mol Reprod Dev 84:444-459
Gervaise, Amanda L; Arur, Swathi (2016) Spatial and Temporal Analysis of Active ERK in the C. elegans Germline. J Vis Exp :
Snee, Mark J; Wilson, William C; Zhu, Yi et al. (2016) Collaborative Control of Cell Cycle Progression by the RNA Exonuclease Dis3 and Ras Is Conserved Across Species. Genetics 203:749-62
McCallum, Katie C; Liu, Bin; Fierro-González, Juan Carlos et al. (2016) TRX-1 Regulates SKN-1 Nuclear Localization Cell Non-autonomously in Caenorhabditis elegans. Genetics 203:387-402
Arur, Swathi (2015) Context-dependent regulation of Dicer activity and small RNA production: Implications to oocyte-to-embryo transition. Worm 4:e1086062

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